Marie H. Hanigan


Professor, Department of Cell Biology
Adjunct Professor, Department of Obstetrics and Gynecology


B.S. cum laude Zoology, Duke University, Durham, North Carolina
Ph.D. Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI


The American Association for Cancer Research
Women in Cancer Research
American Association for the Advancement of Science


Sensitizing Tumors to Chemotherapy: Inhibition of Gamma Glutamyl Transpeptidase

Many tumors respond initially to chemotherapy but with continued treatment become resistant to the drugs. One of the most common mechanisms by which tumors develop resistance to chemotherapy is by inactivating the drugs with glutathione. We have shown that expression of the enzyme gamma-glutamyl transpeptidase (GGT) on the surface of the tumor cell enables the tumors to use extracellular glutathione as a source of cysteine. During treatment with chemotherapy the intracellular levels of glutathione are depleted and the intracellular concentration of cysteine can become rate-limiting for glutathione synthesis. Tumor cells that express GGT are resistant to chemotherapy drugs such cisplatin. We are developing inhibitors of GGT that can be used clinically to block GGT-mediated drug resistance. We identified a novel inhibitor of GGT that is the first uncompetitive inhibitor of GGT ever reported (JBC 284:9059, 2009). We continue to develop inhibitors of GGT that can be used in the clinic.  


Structural Studies of Gamma Glutamyl Transpeptidase

To aid our studies on the development of a GGT inhibitor, we collaborated with Dr. Blaine Mooers at OUHSC, crystallized human GGT and determined its structure [J. Biol. Chem., 288(44):31902-31913, 2013]. Human GGT is a heavily glycosylated, membrane bound enzyme which presented challenges in the crystallization. This is the first structure to be determined for any eukaryotic GGT. We are using this structure to aid in the design of more potent inhibitors of human GGT. 


Crystal structure of human GGT. A, ribbon representation of the hGGT1 heterodimer. Shown are the large subunit (blue), the small subunit (green), and the active site Thr-381 (red). The orange oval outlines the active site cleft. For details see J. Biol. Chem., 288(44):31902-31913, 2013

Cancer Biomarkers

Tumors that are detected at an early stage are most responsive to treatment and in some cases can be cured surgically. However, for many of the most deadly cancers including liver, pancreatic and kidney cancer there are no routine screening tests that can be used to detect the tumor at an early stage. We are developing biomarkers that can be detected in the blood or the urine. We are focusing on the differences in glycosylation between normal cells and tumor cells. We have recently completed an in-depth characterization of the N-glycans on GGT expressed in normal human kidney and liver (JBC, 2010). We are now analyzing the glycans on GGT from tumor cells to identify glycopeptides that can be used as biomarkers for early detection of these often fatal tumors.   





Terzyan, S.S., Burgett, A.W., Heroux, A., Smith, C.A., Mooers, B.H., and Hanigan, M.H. (2015) Human Gamma-Glutamyl Transpeptidase 1: Structures of the Free Enzyme, Inhibitor-Bound Tetrahedral Transition States and Glutamate-Bound Enzyme Reveal Novel Movement within the Active Site during Catalysis. J Biol Chem. 2015 May 26. pii: jbc.M115.659680. [Epub ahead of print]


Hanigan, M.H., Gillies, E.M., Wickham, S., Wakeham, N., and Wirsig-Wiechmann, C.R. (2015) Immunolabeling of gamma-glutamyl transferase 5 in normal human tissues reveals that expression and localization differ from gamma-glutamyl transferase 1. Histochem. Cell Biol. 143(5): 505-515. [PMCID 439375]


West, M.B., Partyka, K., Feasley, C.L., Maupin, M.A., Goppallawa, I., West, C.M., Haab, B.B. and  Hanigan, M.H. (2014) Detection of Distinct Glycosylation Patterns on Human Gamma-Glutamyl Transpeptidase 1 Using Antibody-Lectin Sandwich Array (ALSA) Technology. BMC Biotechnology, Dec 6;14(1):101. PMCID: PMC4297448


Hanigan, M.H. (2014) Gamma-glutamyl transpeptidase: redox regulation and drug resistance. Advances in Cancer Research 122:103-41. PMCID:PMC4388159


West, M.B., Wickham, S., Parks, E.E., Sherry, D.M. and Hanigan, M.H. (2013) Human GGT2 Does Not Autocleave into a Functional Enzyme: A cautionary tale for interpretation of microarray data on redox signaling. Antioxidants & Redox Signaling, 19(16):1877-1888. PMCID:PMC3852618

(Image from publication used for cover of December 1, 2013 issue of Antioxidants & Redox Signaling)


West, M.B.,  Chen, Y., Wickham, S., Heroux, A.,  Cahill, K., Hanigan, M.H., Mooers, B.H.M. (2013) Novel insights into eukaryotic gamma-glutamyl transpeptidase 1 from the crystal structure of the glutamate bound human enzyme. J. Biol. Chem. 288(44):31902-31913. PMCID:PMC3814782


Wickham, S., Regan, N., West, N.B., Thai, J., Cook, P.F., Terzyan, S.S., Li, P-K., and Hanigan, M.H. (2013) Inhibition of Human Gamma-Glutamyl Transpeptidase: Development of More Potent, Physiologically Relevant, Uncompetitive Inhibitors. Biochemical Journal, 450(3):547-57. PMCID: PMC3836663


Wickham, S., Regan, N., West, M.B., Kumar, V.P., Thai, J., Li, P-K, Cook, P.F., Hanigan, M.H. (2012) Divergent Effects of Compounds on the Hydrolysis and Transpeptidation Reactions of Gamma-Glutamyl Transpeptidase. Journal of Enzyme Inhibition and Medicinal Chemistry 27, 476-489. PMCID:PMC3407035


Wickham, S., West, M.B., Cook, P.F, and Hanigan, M.H. (2011) Gamma-Glutamyl Compounds: Substrate Specificity of Gamma-Glutamyl Transpeptidase Enzymes. Analytical Biochemistry, 414:208-214. PMCID:PMC3099546


West, M.B., Wickham, S., Quinalty, L.M., Pavlovicz, R.E., Li, C. and Hanigan. M.H. (2011) Autocatalytic Cleavage of Human g-Glutamyl transpeptidase Is Highly Dependent on N-Glycosylation at Asparagine 95  J. Biol. Chem., 286 (33):28876-88. PMCID:PMC3190695



Tax deductible contributions to help support this research can be made to: OU Foundation Inc, The Cell Biology Cancer Research Fund,  Account #50701, University of Oklahoma, Alumni and Development Office, P.O. Box 26901, 162 Library, Oklahoma City, Oklahoma 73126-9968.



University of Oklahoma Health Sciences Center
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